Clozaril

"Feb. 22, 2011 -- The FDA has issued a safety announcement notifying health care professionals that it has updated the pregnancy section of drug labels for the entire class of antipsychotic medications.

Clozaril

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of
clozapine is unknown. However, it has been proposed that the therapeutic
efficacy of clozapine in schizophrenia is mediated through antagonism of the
dopamine type 2 (D2) and the serotonin type 2A (5-HT2A) receptors. Clozaril
also acts as an antagonist at adrenergic, cholinergic, histaminergic and other
dopaminergic and serotonergic receptors.

Clinical electroencephalogram
(EEG) studies demonstrated that clozapine increases delta and theta activity
and slows dominant alpha frequencies. Enhanced synchronization occurs. Sharp
wave activity and spike and wave complexes may also develop. Patients have
reported an intensification of dream activity during clozapine therapy. REM
sleep was found to be increased to 85% of the total sleep time. In these
patients, the onset of REM sleep occurred almost immediately after falling
asleep.

Pharmacokinetics

Absorption

In man, CLOZARIL tablets (25 mg and 100 mg) are equally
bioavailable relative to a CLOZARIL solution. Following oral administration of
CLOZARIL 100 mg twice daily, the average steady-state peak plasma concentration
was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours
(range: 1 to 6 hours) after dosing. The average minimum concentration at steady
state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing.
Food does not appear to affect the systemic bioavailability of CLOZARIL. Thus,
CLOZARIL may be administered with or without food.

Distribution

Clozapine is approximately 97% bound to serum proteins.
The interaction between clozapine and other highly protein-bound drugs has not
been fully evaluated but may be important [see DRUG INTERACTIONS].

Metabolism and Excretion Clozapine is almost completely
metabolized prior to excretion, and only trace amounts of unchanged drug are
detected in the urine and feces. Clozapine is a substrate for many cytochrome
P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Approximately 50% of
the administered dose is excreted in the urine and 30% in the feces. The
demethylated, hydroxylated, and N-oxide derivatives are components in both
urine and feces. Pharmacological testing has shown the desmethyl metabolite
(norclozapine) to have only limited activity, while the hydroxylated and N-oxide
derivatives were inactive. The mean elimination half-life of clozapine after a
single 75 mg dose was 8 hours (range: 4 to12 hours), compared to a mean
elimination half-life of 12 hours (range: 4-66 hours), after achieving steady
state with 100mg twice daily dosing.

A comparison of single-dose and multiple-dose administration
of clozapine demonstrated that the elimination half-life increased
significantly after multiple dosing relative to that after single-dose
administration, suggesting the possibility of concentration-dependent
pharmacokinetics. However, at steady state, approximately dose-proportional
changes with respect to AUC (area under the curve), peak, and minimum clozapine
plasma concentrations were observed after administration of 37.5, 75, and 150
mg twice daily.

Drug-Drug Interaction Studies

Fluvoxamine

A pharmacokinetic study was conducted in 16 schizophrenic
patients who received clozapine under steady-state conditions. After
coadministration of fluvoxamine for 14 days, mean trough concentrations of
clozapine and its metabolites, N-desmethylclozapine and clozapine N-oxide, were
elevated about three-fold compared to baseline steady state concentrations.

Paroxetine, Fluoxetine, and Sertraline

In a study of schizophrenic patients (n=14) who received
clozapine under steady-state conditions, coadministration of paroxetine
produced only minor changes in the levels of clozapine and its metabolites.
However, other published reports describe modest elevations (less than
two-fold) of clozapine and metabolite concentrations when clozapine was taken
with paroxetine, fluoxetine, and sertraline.

Specific Population Studies

Renal or Hepatic Impairment

No specific pharmacokinetic studies were conducted to
investigate the effects of renal or hepatic impairment on the pharmacokinetics
of clozapine. Higher clozapine plasma concentrations are likely in patients
with significant renal or hepatic impairment when given usual doses.

CYP2D6 Poor Metabolizers

A subset (3%–10%) of the population has reduced activity
of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than
expected plasma concentrations of clozapine when given usual doses.

Clinical Studies

Treatment Resistant Schizophrenia

The efficacy of CLOZARIL in treatment-resistant
schizophrenia was established in a multicenter, randomized, double-blind,
active-controlled (chlorpromazine) study in patients with a DSM-III diagnosis
of schizophrenia who had inadequate responses to at least 3 different
antipsychotics (from at least 2 different chemical classes) during the preceding
5 years. The antipsychotic trials must have been judged adequate; the
antipsychotic dosages must have been equivalent to or greater than 1000 mg per
day of chlorpromazine for a period of at least 6 weeks, each without
significant reduction of symptoms. There must have been no period of good
functioning within the preceding 5 years. Patients must have had a baseline
score of at least 45 on the investigator-rated Brief Psychiatric Rating Scale
(BPRS). On the 18-item BPRS, 1 indicates the absence of symptoms, and 7
indicates severe symptoms; the maximum potential total BPRS score is 126. At
baseline, the mean BPRS score was 61. In addition, patients must have had a
score of at least 4 on at least two of the following four individual BPRS
items: conceptual disorganization, suspiciousness, hallucinatory behavior, and
unusual thought content. Patients must have had a Clinical Global Impressions –
Severity Scale score of at least 4 (moderately ill).

In the prospective, lead-in phase of the trial, all
patients (N=305) initially received single-blind treatment with haloperidol
(the mean dose was 61 mg per day) for 6 weeks. More than 80% of patients
completed the 6-week trial. Patients with an inadequate response to haloperidol
(n=268) were randomized to double-blind treatment with CLOZARIL (N=126) or
chlorpromazine (N=142). The maximum daily CLOZARIL dose was 900 mg; the mean
daily dose was > 600 mg). The maximum daily chlorpromazine dose was 1800 mg;
the mean daily dose was > 1200 mg.

The primary endpoint was treatment response, predefined
as a decrease in BPRS score of at least 20% and either (1) a CGI-S score of ≤ 3
(mildly ill), or (2) a BPRS score of ≤ 35, at the end of 6 weeks of
treatment. Approximately 88% of patients from the CLOZARIL and chlorpromazine groups
completed the 6-week trial. At the end of six weeks, 30% of the CLOZARIL group
responded to treatment, and 4% of the chlorpromazine group responded to
treatment. The difference was statistically significant (p < 0.001). The
mean change in total BPRS score was -16 and -5 in the CLOZARIL and
chlorpromazine group, respectively; the mean change in the 4 key BPRS item
scores was -5 and -2 in the CLOZARIL and chlorpromazine group, respectively;
and the mean change in CGI-S score was -1.2 and -0.4, in the CLOZARIL and
chlorpromazine group, respectively. These changes in the CLOZARIL group were
statistically significantly greater than in the chlorpromazine group (p <
0.001 in each analysis).

The effectiveness of CLOZARIL in reducing the risk of
recurrent suicidal behavior was assessed in the International Suicide
Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals
Corporation). This was a prospective, randomized, open-label,
active-controlled, multicenter, international, parallel-group comparison of
CLOZARIL versus olanzapine (Zyprexa®, a registered trademark of Eli Lilly and
Company) in 956 patients with schizophrenia or schizoaffective disorder
(DSM-IV) who were judged to be at risk for recurrent suicidal behavior. Only
about one-fourth of these patients (27%) were considered resistant to standard
antipsychotic drug treatment. To enter the trial, patients must have met one of
the following criteria:

They had attempted suicide within the three years prior
to their baseline evaluation.

They had been hospitalized to prevent a suicide attempt
within the three years prior to their baseline evaluation.

They demonstrated moderate-to-severe suicidal ideation
with a depressive component within one week prior to their baseline evaluation.

They demonstrated moderate-to-severe suicidal ideation
accompanied by command hallucinations to do self-harm within one week prior to
their baseline evaluation.

Dosing regimens for each treatment group were determined
by individual investigators and were individualized by patient. Dosing was
flexible, with a dose range of 200– 900 mg/day for CLOZARIL and 5–20 mg/day for
olanzapine. For the 956 patients who received CLOZARIL or olanzapine in this
study, there was extensive use of concomitant psychotropics: 84% with
antipsychotics, 65% with anxiolytics, 53% with antidepressants, and 28% with
mood stabilizers. There was significantly greater use of concomitant
psychotropic medications among the patients in the olanzapine group.

The primary efficacy measure was time to (1) a
significant suicide attempt, including a completed suicide; (2) hospitalization
due to imminent suicide risk, including increased level of surveillance for
suicidality for patients already hospitalized; or (3) worsening of suicidality
severity as demonstrated by “much worsening” or “very much worsening” from
baseline in the Clinical Global Impression of Severity of Suicidality as
assessed by the Blinded Psychiatrist (CGI-SS-BP) scale. A determination of
whether or not a reported event met criterion 1 or 2 above was made by the
Suicide Monitoring Board (SMB), a group of experts blinded to patient data.

A total of 980 patients were randomized to the study and
956 received study medication. Sixty-two percent of the patients were diagnosed
with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective
disorder. Only about one-fourth of the total patient population (27%) was
identified as “treatment-resistant” at baseline. There were more males than
females in the study (61% of all patients were male). The mean age of patients
entering the study was 37 years of age (range 18–69). Most patients were
Caucasian (71%), 15% were Black, 1% were Asian, and 13% were classified as
being of “other” races.

Patients treated with CLOZARIL had a statistically
significant longer delay in the time to recurrent suicidal behavior in
comparison with olanzapine. This result should be interpreted only as evidence
of the effectiveness of CLOZARIL in delaying time to recurrent suicidal
behavior and not a demonstration of the superior efficacy of CLOZARIL over
olanzapine.

The probability of experiencing (1) a significant suicide
attempt, including a completed suicide, or (2) hospitalization because of
imminent suicide risk, including increased level of surveillance for
suicidality for patients already hospitalized, was lower for CLOZARIL patients
than for olanzapine patients at Week 104: CLOZARIL 24% versus olanzapine 32%;
95% CI of the difference: 2%, 14% (Figure 2).

Figure 2: Cumulative Probability of a Significant
Suicide Attempt or Hospitalization to Prevent Suicide in Patients with Schizophrenia
or Schizoaffective Disorder at High Risk of Suicidality

Last reviewed on RxList: 8/2/2013
This monograph has been modified to include the generic and brand name in many instances.